A recent EMA guidelineclarifies the structure, content, method, and duration of archiving of clinical trial documents. Exom Group offers Genius eDocumentum, a digital archiving solution that meets regulatory requirements.

During the conduct of clinical studies, it is necessary to maintain an archive, whether paper or electronic, called the Trial Master File (TMF). This is the collection of essential documents used by Sponsor, CRO, and Investigators for the management of the study. 

It also serves to monitors, auditors, and inspectors to review and verify whether the Sponsor and the Investigators conducted the trial in line with the study protocol and applicable regulatory requirements and GCP standards.

 

EMA viewpoint of TMF management and archiving

In December 2018, EMA issued a guideline on the content, management and archiving of the TMF to help Sponsors and Investigators in complying with the requirements of the existing legislation (Directive 2001/20/EC and Directive 2005/28/EC), and with the rules of Good Clinical Practice ICH E6.

The topic we want to deal with in this post concerns only the method and period of preservation of the TMF documents, once the study is finished.

What the European regulation says?

As required by the new European Regulation, the content of the TMF must be archived in a way that ensures that it is readily available and directly accessible, upon request, by a regulatory authority. In addition, any changes or modifications to the content of the TMF must be tracked.

Access to archived data/documents should be properly controlled and limited by means of user access profiles to the electronic storage area on servers or by means of physical access control to the paper storage place. In addition, electronic documents or stored data should be protected from unauthorised modification in order to maintain their authenticity.

It is also important that access to documents and data is maintained throughout the storage period. This includes ensuring system maintenance (hardware and software) to access data in the original archived format, or the use of a new system to emulate old software, or the migration of data into a new format to ensure continuous access with new software. This issue should be addressed through written procedures by the organisation responsible for long-term archiving.

According to the EMA the long-term archiving of the TMF can be either through an external archive that provides the preservation of paper documents or through an electronic archiving (eg, cloud data center). When an external repository is used, the sponsor must still make an assessment of the suitability of the solution used both before use and periodically during the long-term archiving period.

How long should the TMF be stored?

As there is not yet a certain date of application of the new European regulation, the answer to this question is articulated.

For studies conducted under Directive 2001/20/EC, Sponsor and Investigator must ensure that the documents contained in the TMF are retained for at least 5 years after the end of the trial or in accordance with national regulations.

However, trials in which data are used to support a marketing authorisation have additional requirements and the TMF must be retained for at least 15 years after completion or suspension of the trial or at least two years after the last marketing authorisation has been granted in the European Community (where no marketing authorisation applications are pending or foreseen in the EC) or at least two years after the formal suspension of the clinical development of the investigational product (Directive 2003/63/EC)

For clinical studies that do not fall in time as required by Article 98 of the new European Regulation, Directive 2003/63/EC (amending Directive 2001/83/EC) applies, which states that “the sponsor or other owner of the data must keep a part of the documentation relating to the trial for as long as the product is authorized. This documentation should include the study protocol, standard operating procedures, standard operating procedures, all written opinions on the protocol and procedures, the investigator’s brochure, case report forms on each trial subject, final report and audit certificate(s), if available. The final report shall also be retained by the sponsor or subsequent owner, for five years after the medicinal product is no longer authorised.

What happens with the eforcement of the new Regulation

As soon as the new European regulation becomes effective, in accordance with Article 58, unless other provisions of Union law require a longer storage period, the sponsor and the investigator will have to archive the content of the clinical TMF for at least 25 years after the end of the clinical trial. However, the subject’s medical records at the trial site shall be archived in accordance with national law.

Therefore, it is the sponsor’s responsibility to determine which requirements apply to the respective clinical trial in relation to the start and end dates and whether the trial is used, or intended to be used, to support a marketing authorisation, as the retention requirements are dependent on these factors.

Finally, it should not be forgotten that the requirements and methods of storage of documentation and medical records held by the investigator and the institution should be formalized, through a written agreement between the sponsor and the investigational sites.

Genius eDocumentum: Exom Group’s solution for long-term archiving

It is a validated cloud service that enables secure, long-term storage of documents and clinical trial data, after completion, accessible online for instant viewing and sharing between authorized users and auditors in the event of inspections or requests.

Genius eDocumentum enables the creation of electronic certified copies defined as the electronic copies of the original paper documents that have been verified (e.g. by a dated signature) or have been generated through a validated process to produce an exact copy having all the same information, including data that describe the context, content and structure, as the original.

The creation of certified copies, meeting the requirements described above, eliminates the need to archive the original paper documents separately and outside the Genius eDocumentum digital platform.

Through a controlled and validated procedure, at the end of the study, documents and data are quickly transferred from the electronic TMF and eCRF to the long-term electronic archive, allowing 24/7 read-only access to authorised users.

Conclusions

Maintaining the data and documents of a clinical trial both during and after its conclusion is not only a regulatory obligation and by GCPs but must be done in accordance with a number of technical requirements. Requirements that a digital archiving with Genius eTMF first and with Genius eDocumentum then can guarantee.

All with maximum flexibility, security, and without any risk of deterioration and/or obsolescence of the electronic medium over the years.

Telemedicine, the importance of reliable data

The lack of diversity in clinical trials has widespread implications. Most of the cancer drugs used today are developed on the basis of clinical data that are representative of less than 5% of cancer patients. In both Europe and the United States, ethnic or racial minorities are very widespread and represented, but patients participating in clinical trials for new drugs are in some cases strongly white, from 80 to 90 percent.

Clinical conditions such as heart disease, cancer, and diabetes, as well as therapeutic responses, vary by ethnicity, as well as between the sexes. If different groups of patients are not part of these studies, we cannot be sure if the treatment will work in all populations or what side effects might emerge in one group or another.

Technological solutions such as telemedicine, which reduce the obstacles and burden of participation in clinical trials, together with the availability of devices that allow various clinical parameters to be measured at the patient’s home, promote the diversity of the study population and allow the evaluation of therapeutic efficacy in the real world and thus to record completely new and patient-centred endpoints in areas of need not yet satisfied.

Already in June 2017, the CTTI (Clinical Trial Transformation Initiative), an organization that includes representatives of the FDA, pharmaceutical and biotech companies, CRO, ethics committees, academic institutions and patient groups, published a document entitled “Developing novel endpoints generated by mobile technology for use in clinical trials”, which contains recommendations for conducting studies focused on the patient through the use of mobile digital technologies, also providing concrete suggestions on how to organize this type of studies in certain diseases.

 

Genius Rosa, the telemedicine solution from Exom Group

Exom Group offers a sophisticated telemedicine platform, called Genius ROSA,  configured for use in clinical trials. Genius Rosa is a multichannel, private, encrypted application, specific for clinical trials, for direct communication between doctor and patient and for remote monitoring of the patient’s clinical condition. Both the investigator and the patient use their own device (BYOD), a PC or a smartphone through an app, and the system operates through standard and familiar digital communication solutions, such as audio-video calls, chats, and text messages.

The system can send reminders (e.g. text messages, e-mails) to the patient or use automatic alerts when a specific study activity is to be performed (e.g. when a dose of medication is to be taken, or a remote visit is planned or measurements and exercises are to be performed).  The patient can respond to electronic questionnaires (ePRO) from home and the data are automatically saved in the study database. Obviously, both the automatic alerts and the content of the information to be shared with the patient can be defined and adapted according to the characteristics of the study and the required language.

Genius ROSA can collect measured data from different devices at the patient’s home and send them directly to the study database through a secure and encrypted transmission. So far, more than 50 different devices are integrated into the Genius ROSA, from glucometers to spirometers, and many more.

The integration of Genius ROSA with the study’s eCRF and Genius ENGAGE application, for electronic informed consent, avoids the risk of collecting patient data both at the center and remotely, before the patient has signed the consent for participation in the study.

 

Conclusion

In conclusion, Genius ROSA is the ideal solution both to facilitate the enrolment of patients while respecting the ethnic-biological diversity of the population and to put the patient himself at the center of the clinical study. Its use is therefore very much indicated in rare diseases, oncology, pediatrics, chronic diseases, and elderly patients.

Ultimately, Genius ROSA reduces the overall costs of the study as well as the discomfort of the patient for repeated visits to the study center and ensures evaluation of the effectiveness of the treatment in the real-life conditions of the patient.

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